Isoflavones are a group of vegetable dyes belonging to the flavonoids and are derived from isoflavones. The following isoflavones are particularly important:
 573′4′1IsoflavonHHHH2DaidzeinHOHHOH3GenisteinOHOHHOH4PrunetinOHOCH3HOH5Biochanin AOHOHHOCH36OrobolOHOHOHOH7SantalOHOCH3OHOH8PratenseinOHOHOHOCH3
One of the most important isoflavones is genistein.
Genistein is a well-known pharmaceutically and cosmetically active ingredient which has anti-bacterial activity. Genistein is a calmodulin-antagonist, and of particular importance is the enzyme-inhibitory activity of genistein e.g. against tyrosine kinases, dopa-carboxylases, etc. Genistein can also be used in insecticides. The chemical name of genistein is 4′,5,7-trihydroxyisoflavone, and the compound can be obtained by purification from natural products, such as soy products (e.g. Biochem. Biophys. Res. Commun. 179:661-667, 1991), but it can also be chemically synthesized by methods known in the art. Genistein is commercially available from many suppliers and in a high purity. The chemical structure of genistein is as follows:

A significant number of publications are directed to genistein and the use thereof, and it can e.g. be referred to U.S. Pat. No. 5,824,702, WO 03/068218 or U.S. Pat. No. 5,948,814, to mention only three recent ones of the numerous patents and patent applications in this field.
Genistein is normally produced in crystalline powder form e.g. according to a process as disclosed in WO 2004/009576. Such a powder form has a very poor flowability. The poor powder flowability renders the crystalline powder difficult for use in making tablets and other application forms that require the powder to be free flowing. The same problem occurs if one tries to make formulations with other isoflavones.
Furthermore, it is difficult to include isoflavones, in particular genistein e.g. in food supplements in a reasonably high concentration and in a form which provides a high bioavailability of the isoflavone (or genistein).
These problems are particularly addressed in WO 99/38509, which suggests solving these problems by coupling e.g. the Genistein with an amphiphilic carrier to form a micelle having an average diameter of less than about 100 nm. The amphiphilic carriers disclosed in this document are essentially polyethyleneglycolyzed fatty acid glycerides such as those obtained from fully or partially hydrogenated various vegetable oils.
However, such micelles are difficult to obtain and their field of application is rather limited and only nutritional supplements are disclosed in WO 99/38509.
Regarding topical application forms, despite the numerous documents describing genistein and its applications, the presently marketed topical compositions with genistein either contain only very low concentrations of genistein, such as 0.01 wt.-% or less, or contain an organic solubilizer or solvent for genistein, such as ethanol. The presence of organic solvents such as ethanol in topical compositions should, however, be avoided, if possible, since some organic solvents such as ethanol can cause skin irritations.
If one prepares a topical composition which is solely based on water as a solvent and contains higher concentrations of commercially available genistein, such as more than 0.1 wt.-%, in particular more than 0.2 wt.-% or 0.5 wt.-% or more genistein, such a topical composition becomes gritty during storage. Applying such a gritty topical composition to the skin can cause irritations, and the consumer acceptance is low, in particular, if the composition is a cosmetic composition. Furthermore, together with becoming gritty the activity of the genistein in the aqueous topical formulation can decrease upon storage.
Nanosuspensions of water-insoluble pharmaceutically active compounds and methods of preparing such nanosuspensions are known in the art, and it can be referred e.g. to U.S. Pat. No. 5,858,410 and U.S. Pat. No. 5,145,684. These documents disclose many possible active ingredients which can be provided in the form of nanosuspensions, but they are quiet on genistein. Both documents are mainly concerned with a method to increase the bioavailability of a drug, and they do not address topical compositions and problems which occur in topical compositions.
Furthermore, there exist several review articles on drug nanoparticles or micron-sized drug particles, e.g. “Advanced Drug Delivery Reviews 47 (2001) 3-19”. This document discloses that providing a drug in the form of nanoparticles might increase the saturation solubility and the dissolution velocity of the drug. The document is mainly concerned with the bioavailability of water-insoluble drugs which are for oral or parenteral administration. Topical formulations and problems which might occur in topical formulations are not disclosed. Genistein is not disclosed.
Another review article “Pharmaceutical Development and Technology, Vol. 9, No. 1, pages 1-13, 2004” compares the different processes for producing micron-sized drug particles and their advantages and disadvantages. According to the document, the production of small dry particles is still a challenge, and some problems are discussed which occur, in particular if the small particles are prepared by comminution of bigger dry particles and not by association of molecularly dispersed drug. While the document generally mentions that micronized drugs can be used for intravenous, topical, oral or ophthalmic compositions, the main focus is on pulmonary dry administration and improvement of the bioavailability of poorly water-soluble drugs. Apart from the above general information, topical compositions are not mentioned and genistein is not mentioned either.
Considering the wide application of isoflavones and in particular of genistein in topical and oral compositions, in solid and liquid compositions, in the pharmaceutical, cosmetic and nutritional industry, there is a need to provide isoflavones, and in particular genistein in a form which can easily be handled and formulated into all kinds of application forms, not only at a high concentration in oral compositions but also in topical compositions.
It is thus an object of the present invention to provide isoflavones and in particular genistein in a form which meets the above need.
In particular the isoflavones, such as genistein, should be provided in a form which makes it possible to prepare topical aqueous compositions, in particular topical aqueous cosmetic compositions, which are preferably free of ethanol and preferably also free of other organic solvents, and which contain the isoflavone (particularly the genistein) in a high concentration of more than 0.01 wt.-%, but preferably in even much higher concentrations such as 0.3 wt.-% or more. The compositions should be stable during storage for at least three months, preferably for at least six months, more preferably for at least one year and not develop grittyness during this time.
The isoflavones such as the genistein should also be provided in a form which is particularly suitable for food and food additives or beverages or health food such as tofu, yogurt, orange juice etc. where a high bioavailability, mixability, content uniformity, physical stability etc. must be provided.